Pregnancy and Breast Cancer - Green-top Guideline No. 12 March 2011
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Pregnancy and Breast Cancer Green–top Guideline No. 12 March 2011
Pregnancy and Breast Cancer This title was first published as RCOG advice in 1997 and subsequently as a Green-top Guideline in January 2004.This document is the second edition of the guideline and updates the previous 2004 edition. 1. Purpose and scope This document aims to provide clinical guidance to health professionals caring for women of childbearing age with a diagnosis or history of breast cancer.The management of pregnancy in relation to breast cancer is multidisciplinary.The guideline will be of value to obstetricians and gynaecologists, fertility specialists and midwives as well as oncologists and breast care nurses. 2. Background Breast cancer is the most common cancer in females, with a lifetime risk of one in nine in the UK, and is the leading cause of death in women aged 35–54 years. Fifteen percent of cases are diagnosed before the age of 45 years, thus breast cancer affects almost 5000 women of reproductive age in the UK annually. Between 1991 and 1997 there were 1.3–2.4 cases of breast cancer in women per 10 000 live births,1,2 although when breast cancer is diagnosed in women aged 30 years or less, 10–20% of cases may be associated with pregnancy or occur within 1 year postpartum. The prognosis of breast cancer is improving, with 5-year survival around 80% for the under 50s age group; however, the survival rate may be lower in very young women.3 Treatment of pregnancy-associated cancer should be in a multidisciplinary team according to standard UK guidelines4 with inclusion of the obstetric team as core members. Fewer than 10% of women diagnosed with breast cancer subsequently become pregnant,5,6 but increasing numbers of women are seeking pregnancy following treatment.Young women presenting with breast cancer often have fertility-related concerns7–9 and need well-informed discussions on fertility, pregnancy and lactation after breast cancer and the availability of fertility preservation procedures. 3. Identification and assessment of evidence This guideline was developed in accordance with standard methodology for producing RCOG Green-top Guidelines.Medline,Pubmed,all EBM reviews (Cochrane CRCT, Cochrane Database of Systematic Reviews, Methodology register, ACP journal club, DARE, HTA, Maternity and Infant Care), EMBASE and TRIP were searched for relevant randomised controlled trials,systematic reviews and meta-analyses,cohort studies and case studies.The search was restricted to articles published between 2002 and December 2009, updated from the original search for the previous edition.The search terms included were:‘breast neoplasms’, ‘breast cancer’,‘pregnancy’,‘pregnancy complications’,‘breast cancer and fertility’,‘mastectomy’,‘breast- feeding’,‘lactation’,‘contraception’,‘fertility’and‘infertility’.Abstracts were used to identify key articles.The National Library for Health and the National Guidelines Clearing House were searched for relevant guidelines. In contrast to the extensive literature on treatment of breast cancer, there is no level 1 evidence on pregnancy and breast cancer.There are some well-designed observational studies.Thus, recommendations for practice are limited to grade C/D but, where possible, recommendations are based on, and explicitly linked to, the evidence that supports them.Areas lacking evidence are highlighted and annotated as ‘good practice points’. RCOG Green-top Guideline No. 12 2 of 15 © Royal College of Obstetricians and Gynaecologists
4. What is the optimal management of breast cancer diagnosed during pregnancy?
4.1 Prognosis
Pregnancy itself does not appear to worsen the prognosis for women diagnosed in pregnancy
Evidence
compared with non-pregnant controls matched for age and stage10 (provided that standard level 2–
treatment guidelines for the breast cancer are adhered to).
However, as pregnancy-associated breast cancer occurs in a younger population who may have
Evidence
features that carry a higher risk of metastases such as high-grade tumours and estrogen receptor level 2+/3
negative tumours, these younger women may be expected to have an inferior prognosis.11,12
4.2 Diagnosis
Women presenting with a breast lump during pregnancy should be referred to a
breast specialist team and any imaging or further tests should be conducted in
conjunction with the multidisciplinary team.
Diagnosis may be difficult in women who are pregnant or lactating.Women presenting with a breast lump
during pregnancy should be referred to a breast specialist team and any imaging or further tests should
be conducted within the breast multidisciplinary team. Women should have a designated key worker,
usually a breast care nurse. Ultrasound is used first to assess a discrete lump, but if cancer is confirmed,
mammography is necessary (with fetal shielding) to assess the extent of disease and the contralateral
breast.Tissue diagnosis is with ultrasound-guided biopsy for histology rather than cytology, as proliferative
change during pregnancy renders cytology inconclusive in many women.Histology is similar to that in age-
matched non-pregnant counterparts: histological grade, receptor status and human epidermal growth
factor receptor 2 (HER2) inform treatment planning. Staging for metastases is conducted only if there is
high clinical suspicion and should comprise chest X-ray and liver ultrasound if possible. Gadolinium-
enhanced magnetic resonance imaging is not recommended unless there is a specific need for it to
investigate a clinical problem; there are limited data for the use of this imaging method in pregnancy,
although no adverse effects of gadolinium on the fetus have been reported.13 Tumour markers such as
CA15-3, CEA and CA125 are not used in early breast cancer and may be misleading in pregnancy, and are
not recommended.
Bone scanning and pelvic X-ray computed tomography are not recommended
because of the possible effect of irradiation on the fetus.
In women who are not pregnant, X-ray computed tomography (CT) and isotope bone scan are the
preferred methods of investigation to establish or exclude metastases.These methods are not appropriate
in women who are pregnant, in whom chest X-ray and liver ultrasound are preferred. If there is concern
about bone involvement, a plain film of the relevant area and/or magnetic resonance imaging to minimise
radiation exposure to the fetus is suggested.
4.3 Consideration of termination of pregnancy
The decision to continue the pregnancy should be based on careful discussion of the
cancer prognosis, treatment and future fertility with the woman and her partner and
multidisciplinary team.
4.4 Treatment during pregnancy
The multidisciplinary team review outcome should be forwarded to the obstetric team
and family doctor.
RCOG Green-top Guideline No. 12 3 of 15 © Royal College of Obstetricians and GynaecologistsSurgical treatment including loco-regional clearance can be undertaken in all trimesters. Breast-
conserving surgery or mastectomy can be considered, based on tumour characteristics and
breast size, following multidisciplinary team discussion. Reconstruction should be delayed to
avoid prolonged anaesthesia and to allow optimal symmetrisation of the breasts after delivery. Evidence
level 4
Sentinel node assessment using radioisotope scintigraphy does not cause significant uterine
radiation,14 but blue dye is not recommended as the effect upon the fetus is unknown. Sentinel
node biopsy is indicated in women who have a negative result from a preoperative axillary
ultrasound and needle biopsy. If the axilla is positive, axillary clearance is indicated.
Radiotherapy is contraindicated until delivery unless it is life saving or to preserve organ function (e.g.
spinal cord compression). If necessary, radiotherapy can be considered with fetal shielding or, depending
on gestational age, early elective delivery could be discussed. Routine breast/chest wall radiotherapy can
be deferred until after delivery.
Systemic chemotherapy is contraindicated in the first trimester because of a high rate of fetal
abnormality, but is safe from the second trimester and should be offered according to protocols
defined by the risk of breast cancer relapse and mortality.Anthracyline regimens are safe; there
are fewer data on taxanes, which should be reserved for high-risk (node-positive) or metastatic
Evidence
disease.15–17 Standard antiemetics including 5HT3 serotonin antagonists and dexamethasone level 3
should be used.There are no data on a neurokinin recptor antagonist with very high efficacy in
chemotherapy-induced emesis.There is no evidence for an increased rate of second-trimester
miscarriage or fetal growth restriction, organ dysfunction or long-term adverse outcome with
the use of chemotherapy.17,18
For women in whom tumour characteristics,defined by imaging and core biopsy,mean that chemotherapy
is indicated, a decision may be made to offer neoadjuvant chemotherapy before surgery to allow tumour
downstaging and to facilitate surgery. Occasionally, with a low-risk tumour in which chemotherapy is not
indicated, there may be an indication for mastectomy. In this situation radiotherapy would be deferred.
Tamoxifen and trastuzumab are contraindicated in pregnancy and should not be
used.
D
Tamoxifen is not used until after delivery.Trastuzumab, a monoclonal antibody targeted against
the HER2/neu receptor, is contraindicated during pregnancy because of reported adverse fetal
outcome.19,20 There are no data on other targeted therapies such as vascular endothelial growth
factor antagonists, including bevacizumab. However, there are no compelling oncological
reasons for use of targeted therapies including monoclonal antibodies or small-molecule tyrosine
Evidence
kinase inhibitors during pregnancy as conventional chemotherapy can be used, allowing these level 3
drugs to be reserved for postpartum. Haemopoietic growth factors (granulocyte colony-
stimulating factor) may be employed to ameliorate chemotherapy-induced neutropenia and
have been used extensively in haematological malignancy; their use is recommended to
minimise potential maternal and fetal problems associated with neutropenia.21 Use of these and
other drugs should be discussed with the obstetrician.
4.5 Timing of delivery of the baby
The birth of the baby should be timed after discussion with the woman and the
multidisciplinary team.
Most women can go to full term of pregnancy and have a normal or induced delivery. If early delivery of
the baby is necessary, consideration of corticosteroids for fetal lung maturation is appropriate. However,
birth should be more than 2–3 weeks after the last chemotherapy session to allow maternal bone marrow
recovery and to minimise problems with neutropenia.
RCOG Green-top Guideline No. 12 4 of 15 © Royal College of Obstetricians and Gynaecologists4.6 Lactation
Women should not breastfeed when taking trastuzumab (Herceptin®, Roche) or
tamoxifen, as it is unknown whether these drugs are transmitted in breast milk.
The ability to breastfeed may depend on surgery and whether major ducts have been excised.
Breastfeeding while on chemotherapy is not advised,as the drugs cross into breast milk and may
Evidence
cause neonatal leucopenia with a risk of infection.There should be a time interval of 14 days or level 3
more from the last chemotherapy session to start of breastfeeding to allow drug clearance from
breast milk.22
If chemotherapy is restarted, breastfeeding must cease. A short period of lactation may be
Evidence
psychologically beneficial after a stressful pregnancy and be beneficial to the baby.23 Women level 4
taking tamoxifen should not breastfeed.
Women should not breastfeed when taking trastuzumab as it is unknown whether this drug is transmitted
in breast milk.
5. What are the contraceptive choices for women wishing to avoid pregnancy after
treatment of breast cancer?
Non-hormonal contraceptive methods are recommended.
Women with a history of breast cancer should seek specialist contraceptive advice. Hormonal
contraception is contraindicated in women with current or recent breast cancer (World Health
Organization/UK medical eligibility category 4).24 This advice does not differentiate between
hormone-sensitive and hormone-insensitive tumours. Although hormonal contraception may
Evidence
be considered after at least 5 years free of recurrence (World Health Organization/UK category level 4
3)24 and current evidence allays concerns that long-term oral contraceptive use affects breast
cancer risk,25,26 there is insufficient evidence to support the use of combined or progestogen-
only hormonal contraceptives when alternative non-hormonal methods are suitable and
acceptable.
The levonorgestrel intrauterine system (LNG-IUS: Mirena®, Bayer Healthcare Pharmaceuticals)
may reduce the risk of endometrial abnormalities during tamoxifen therapy,27 but further
evidence is required on its safety in breast cancer survivors. No overall increase in recurrence
risk was found in a retrospective controlled cohort study of LNG-IUS users compared with non- Evidence
users (adjusted hazard ratio 1.86, 95% CI 0.86–4.00),28 although subgroup analysis suggested a level 2+
higher recurrence risk, which was of borderline significance, in women who developed breast
cancer while using LNG-IUS and continued its use (adjusted hazard ratio 3.39, 95% CI 1.01–
11.35).28
6. What advice should be given to women planning pregnancy following breast cancer?
Women planning a pregnancy after treatment for breast cancer should consult their
clinical oncologist, breast surgeon and obstetrician.
Women on tamoxifen are advised to stop this treatment 3 months before trying to conceive because of
the long half-life of the drug, and to have any routine imaging before trying to conceive to avoid the need
for imaging during pregnancy. Women with metastatic disease should be advised against a further
pregnancy as life expectancy is limited and treatment of metastatic disease would be compromised.The
remainder of this section concerns women treated for early-stage disease.
RCOG Green-top Guideline No. 12 5 of 15 © Royal College of Obstetricians and Gynaecologists6.1 Impact of pregnancy on risk of recurrence
Women can be reassured that long-term survival after breast cancer is not adversely
C
affected by pregnancy.
Since many breast cancers are estrogen receptor positive and endocrine responsive, women used to be
advised against pregnancy because of concerns that it would worsen prognosis. However, the evidence
from the published studies is reassuring, showing either no impact on survival or improved survival.
Despite the limitations of the studies, which are mainly retrospective case–control series with limited
numbers,they at least demonstrate that outcome after treatment for breast cancer is not adversely affected
by pregnancy.29,30
The prognosis is good for women with a subsequent pregnancy after early-stage breast cancer.31–33
The published series reflect an improvement in treatment over recent decades. A recent Evidence
level 2+
population-based study in Western Australia from 1982 to 2003 reported survival rates of 92%
at 5 years and 86% at 10 years.6
Several studies show better survival outcome in women who conceive after treatment for breast
cancer.5,6,32,34,35 In the largest series, women who had a full-term pregnancy (n = 199) had a
Evidence
relative risk of death of 0.73 (95% CI 0.54–0.99).5 These findings may be explained by selection level 2+
bias and the ‘healthy mother effect’ described by Sankila:36 healthy women are more likely to
conceive, and women with poor prognosis or early relapse do not embark upon pregnancy.
However, some authors postulate an actual protective effect of pregnancy.6,37
The impact of pregnancy does not seem to be modified by tumour characteristics (e.g. size,
Evidence
hormone receptor status),5 but there are insufficient data to draw firm conclusions. In women level 2+
with BRCA gene mutations, the risks associated with subsequent pregnancy are uncertain.38
6.2 Time interval before pregnancy
Advice on postponement of pregnancy should be individualised and based on
treatment needs and prognosis over time. Most women should wait at least 2 years
after treatment, which is when the risk of cancer recurrence is highest.
Women are generally advised to wait for at least 2 years after treatment for breast cancer before
conception37,39–41 because of the risk of early relapse.The rate of disease recurrence is highest Evidence
in the first 3 years after diagnosis and then declines,42 although late relapses do occur up to 10 level 3
years and more from diagnosis.3
Women with estrogen receptor positive disease should be advised that the recommended duration of
tamoxifen treatment is 5 years.
This advice has been challenged because of the lack of published data showing that postponing
pregnancy has an impact on outcome;6 the literature on recurrent disease also needs to be
Evidence
reviewed in the light of changing treatment regimens and improved understanding of cancer level 2+
subtypes. It has been suggested that women with a good prognosis need not wait 2 years to
become pregnant.6
RCOG Green-top Guideline No. 12 6 of 15 © Royal College of Obstetricians and GynaecologistsAn understanding of the prognostic factors affecting the individual woman – tumour size,grade,
nodal status,estrogen and progesterone receptor and HER2 status – should enable the oncologist
Evidence
to give appropriate advice.43,44 This is of great importance to the woman desiring pregnancy,who level 4
may need to weigh up the benefit of postponing conception, for example to complete
prolonged adjuvant therapy with tamoxifen, against the risk of infertility as a result of delay.
6.3 Outcome of pregnancy
The majority of pregnancies after breast cancer proceed to live birth.There may be an increased
miscarriage rate following breast cancer,45 but the published series are small and not all report
maternal age (a major risk factor for miscarriage) or distinguish between spontaneous
Evidence
miscarriage and induced termination.31,46,47 A recently reported series of 465 pregnant women level 3
who were breast cancer survivors resulted in 236 full-term births (51%),36 spontaneous miscar-
riages (8%) and 193 induced terminations (41%).5 Women are more likely to terminate a
pregnancy when it occurs soon after treatment or during adjuvant therapy.5,6
Women can be reassured concerning the risk of malformation in children conceived
after treatment for breast cancer.
D
Most of the available data do not show any increase in congenital malformations or stillbirth
among the offspring of women who have completed treatment for breast cancer.6,48,49 A large
study derived from the Danish registries identified 216 births to women with a prior diagnosis
of breast cancer and found no stillbirths, no increase in congenital anomalies no increase in low Evidence
birth weight and no substantial risk of preterm birth (OR 1.3, 95% CI 0.7–2.2).49 The Swedish level 2+/3
data on 331 births, however, showed a tendency towards an increased risk of malformations
(OR 2.1, 95% CI 1.2–3.7), birth before 32 weeks of gestation (OR 3.2, 95% CI 1.7–6.0) and birth
weight below 1500 g (OR 2.9,95% CI 1.4–5.8);50 nevertheless,adverse outcomes are uncommon.
The heritability of breast cancer is a source of anxiety but does not affect childhood health.Women who
are known to be breast cancer gene (BRCA) carriers may wish to consider preimplantation genetic
diagnosis, which is now available in the UK. However, some young women with a family history indicative
of genetic risk may not wish to undergo testing so as not to compromise their decisions regarding having
a family.
7. What is the optimal management of pregnancy following treatment for breast cancer?
Pregnancy following breast cancer should be jointly supervised by the obstetrician,
oncologist and breast surgeon.
Echocardiography should be performed during pregnancy in women at risk to detect
cardiomyopathy through resting left ventricular ejection fraction or echocardio-
D
graphic fractional shortening.
During pregnancy, a breast treated by surgery/radiotherapy may not undergo hormonal change and the
woman may require a temporary prosthesis. If breast imaging is needed, ultrasound (performed through
the breast multidisciplinary team) is preferred. Metastatic relapse may be harder to detect and common
complaints in pregnancy such as backache can be difficult to assess.
These women may have received adjuvant chemotherapy with anthracyclines (doxorubicin, epirubicin),
which can cause cumulative dose-dependent left ventricular dysfunction and, rarely, cardiomyopathy.51,52
Although cardiac complications during pregnancy are rare in cancer survivors,53 echocardiography should
be performed during pregnancy in women at risk to detect cardiomyopathy through resting left ventricular
ejection fraction or echocardiographic fractional shortening.
RCOG Green-top Guideline No. 12 7 of 15 © Royal College of Obstetricians and GynaecologistsA slightly increased risk of delivery complications (OR 1.5, 95% CI 1.2–1.9) and caesarean Evidence
section (OR 1.3, 95% CI 1.0–1.7) has been reported in breast cancer survivors.50 level 2+
The supervision of pregnancy after breast cancer should be consultant led,but midwifery involvement will
help to normalise care.
8. What advice should be given to women wishing to breastfeed following treatment for
breast cancer?
Women can be reassured that they can breastfeed from the unaffected breast.
There is no evidence that breastfeeding increases the risk of recurrence in women who have
completed treatment for breast cancer. Only one study has reported on survival in relation to Evidence
level 2+
lactation,32 and suggested that breastfeeding was associated with better survival than bottle-
feeding.
Breast-conserving surgery may not inhibit lactation in the affected breast, but radiotherapy
Evidence
causes fibrosis, making lactation unlikely.54–57 There is no evidence that previous chemotherapy level 3
affects the safety of breastfeeding.
In view of the well-recognised benefits of breastfeeding to the baby,23 women who wish to breastfeed
should be encouraged to do so.39,58 Midwifery support helps to establish successful lactation.59
9. What is the effect of breast cancer treatment on the woman’s fertility?
The effect of treatment on fertility should be discussed with all women of repro-
ductive age diagnosed with breast cancer, and written information should be
provided. Referral to a fertility specialist should be available. Specialist counselling
should be available.
Infertility after treatment is a major concern for young women with breast cancer.60–63 In an
American survey of 657 women diagnosed with breast cancer under the age of 40 years, 57%
reported ‘substantial concern’ about becoming infertile and 29% stated that it influenced their
Evidence
treatment decisions.63 In this sample, only 51% felt that their concerns had been adequately level 3
addressed, and several other authors have noted women’s frustration with the paucity of
information available.64–66 Women’s preferred source of information on fertility is consultation
with a fertility specialist backed up by an information booklet.64,67
A recent joint working party of the Royal Colleges of Physicians, Radiologists and Obstetricians
and Gynaecologists in the UK recommended that people with cancer should be fully informed Evidence
of potential gonadotoxicity before treatment, and that specialist psychological support and level 4
counselling should be available.68
9.1 What is the effect of adjuvant chemotherapy on fertility?
Chemotherapy-induced gonadotoxicity may cause permanent amenorrhoea with complete loss
of germ cells,transient amenorrhoea,menstrual irregularity and subfertility.The degree of gonado-
toxicity is dependent on the specific agents used, the cumulative dose administered and the Evidence
woman’s age.Amenorrhoea is reported in 20–70% of premenopausal women with breast cancer,69 level 3
but the rate ranges from less than 5% in women under 30 years of age to 50% in women aged
36–40 years.70 Alkylating agents such as cyclophosphamide have well-recognised gonadotoxicity,
RCOG Green-top Guideline No. 12 8 of 15 © Royal College of Obstetricians and Gynaecologistsand the classic CMF regimen (cyclophosphamide, methotrexate, 5-fluorouracil) causes a higher
Evidence
incidence of amenorrhoea than anthracycline-based regimens such as FEC (5-fluorouracil, level 3
epirubicin, cyclophosphamide).71 The newer taxanes appear to be less gonadotoxic.72
9.2 What is the effect of adjuvant hormonal therapy on fertility?
The agents used for adjuvant hormonal therapy do not in themselves cause long-term effects on fertility.
Tamoxifen (a selective estrogen receptor modulator) often causes menstrual irregularity and there is an
increased risk of endometrial pathology; conception during tamoxifen therapy should be avoided because
of potential teratogenicity, and a ‘washout period’ of 2–3 months is advised. Gonadotrophin-releasing
hormone (GnRH) analogues cause amenorrhoea and profound estrogen deficiency; women may find the
menopausal symptoms worrying,but the effect is entirely reversible.Trastuzumab is a monoclonal antibody
that binds selectively to the HER2 protein expressed by some breast cancers; there is no evidence that it
impairs fertility, but pregnancy is not advised during treatment.
9.3 What advice should be given to the woman about postponement of pregnancy before embarking on further
pregnancy?
Women are generally advised to postpone pregnancy for at least 2 years after treatment and may be advised
to continue tamoxifen for 5 years. However, age is a major determinant of fertility and delay with already
poor ovarian function owing to chemotherapy is likely to lead to infertility.Women in their 30s desiring
pregnancy may wish to discuss the value of prolonged treatment with tamoxifen and consider discontin-
uation after 2–3 years. Resuming treatment with tamoxifen after childbearing has not been studied, but it
is a reasonable strategy.
9.4 Can fertility be preserved before treatment?
There is a rapidly growing literature on preservation of fertility potential before chemotherapy.At present,
only a minority of women of reproductive age undertake fertility-preservation procedures and there are
scarcely any data on long-term outcome.
9.4.1 GnRH analogues
There are insufficient level 1 data to support the routine use of GnRH analogues for
ovarian protection in estrogen receptor positive breast cancer.
GnRH analogues have therapeutic use in hormone-sensitive breast cancer, as they induce
profound ovarian suppression and create a low-estrogen state.Trials are in progress to examine
the effect on fertility potential, although there are concerns that concomitant GnRH analogues
Evidence
may lessen tumour response to chemotherapy in estrogen receptor positive breast cancer.There level 3
are several observational and phase II studies of the use of GnRH analogues during chemo-
therapy with the intention of protecting the oocyte pool from depletion.73 Non-randomised
studies in women with breast cancer (total n = 222) are suggestive of benefit.74–76
A recently reported randomised controlled trial in premenopausal women with breast cancer
found that co-treatment with GnRH analogues during chemotherapy lessened the risk of ovarian Evidence
level 1+
damage (35/39 resumed menses versus 13/39, P < 0.001).77 The uncertainties can be discussed
with the woman by the treating oncologist.
9.4.2 Cryopreservation
Ovarian stimulation for egg or embryo freezing requires careful discussion in light of
unknown long-term risks. Modified stimulation regimes should be considered for
women with estrogen-sensitive breast cancer.
RCOG Green-top Guideline No. 12 9 of 15 © Royal College of Obstetricians and GynaecologistsEmbryo cryopreservation is a well established technique with success rates of at least 20% per
cycle,78 although it is possible that success rates may be lower when oocytes are retrieved from
women with cancer.The time required for ovarian stimulation and egg harvest may postpone
Evidence
chemotherapy, and there is a small risk of procedural complications such as ovarian hyperstim- level 2+
ulation. There is concern that elevated estrogen levels may be deleterious in estrogen receptor
positive breast cancer; to minimise this risk, stimulation regimens with tamoxifen or letrozole,
usually combined with gonadotrophins, are proposed.79,80
Oocyte storage may be offered to women without a partner.Freeze–thaw techniques are rapidly
improving,but there have been only a few hundred births worldwide after use of this technique Evidence
and there are no long-term safety data. Harvesting immature oocytes without requiring a level 3
hormone-stimulated cycle is an attractive proposition, but is not an established technique.81
There are insufficient data to support ovarian tissue storage for fertility preservation
in women with breast cancer; this should be offered only in the context of a research
D
trial.
Cryopreservation of ovarian cortex or the whole ovary has resulted in a small number of
pregnancies after regrafting.82 This remains an experimental technique and tissue storage Evidence
level 3
regulations in the UK have restricted its use.The need for a surgical procedure is a disadvantage,
but this technique does not delay chemotherapy.
Every breast oncology service should have a designated pathway for prompt referral
to a fertility specialist able to offer assisted conception; service provision should not
be dependent on local in vitro fertilistion funding arrangements.
The organisational aspects of the expanding breast oncology service need to be addressed.Prompt referral
is essential; preparations for egg retrieval can be instigated during breast cancer diagnostic procedures
and surgery to minimise delays in starting systemic treatment.The National Institute for Health and Clinical
Excellence83 recommended universal access to sperm, egg and embryo storage for people undergoing
gonadotoxic treatment. However, NHS funding is not available in all areas, and is dependent upon the
primary care trust and the local infertility budget.The oncology referral pathway in the cancer network
does not necessarily coincide with local in vitro fertilisation arrangements.The joint Royal Colleges working
party recommended that adequate funding should be made available.68
9.5 Assisted reproduction after treatment for breast cancer
Fertility treatment after chemotherapy is limited by loss of ovarian reserve.84,85 The stimulation aspect of
in vitro fertilisation carries a theoretical risk as it is a hyperestrogenic state, although of shorter duration
than pregnancy.Women who have chemotherapy-induced menopause can become pregnant with donated
eggs; this requires short-term hormone replacement therapy, which again carries a theoretical risk.
Replacement of cryopreserved embryos is also performed in a medicated hormone replacement therapy
cycle.Women for whom pregnancy is contraindicated may wish to consider surrogacy.
RCOG Green-top Guideline No. 12 10 of 15 © Royal College of Obstetricians and Gynaecologists10. Suggested audit topics
Relatively few women present with pregnancy during or after treatment for breast cancer.
Oncologists may wish to audit:
● what percentage of young women treated for breast cancer have been given information on
contraception and future pregnancy
● outcome of referrals to a fertility specialist.
Gynaecologists may wish to audit:
● outcome of referrals for fertility preservation.
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RCOG Green-top Guideline No. 12 13 of 15 © Royal College of Obstetricians and GynaecologistsAppendix
Classification of evidence levels Grades of recommendations
1++ High-quality meta-analyses, systematic At least one meta-analysis, systematic review or
reviews of randomised controlled trials A randomised controlled trial rated as 1++ and
or randomised controlled trials with a directly applicable to the target population; or
very low risk of bias
A systematic review of randomised controlled
1+ Well-conducted meta-analyses, systematic trials or a body of evidence consisting
reviews of randomised controlled trials principally of studies rated as 1+ directly
or randomised controlled trials with a applicable to the target population and
low risk of bias demonstrating overall consistency of results
1– Meta-analyses, systematic reviews of A body of evidence including studies rated as
randomised controlled trials or B 2++ directly applicable to the target
randomised controlled trials with a high population, and demonstrating overall
risk of bias consistency of results; or
2++ High-quality systematic reviews of case– Extrapolated evidence from studies rated as
control or cohort studies or high-quality 1++ or 1+
case–control or cohort studies with a
very low risk of confounding, bias or A body of evidence including studies rated as
C 2+ directly applicable to the target population
chance and a high probability that the
relationship is causal and demonstrating overall consistency of
results; or
2+ Well-conducted case–control or cohort
studies with a low risk of confounding, Extrapolated evidence from studies rated as
bias or chance and a moderate 2++
probability that the relationship is causal Evidence level 3 or 4; or
D
2- Case–control or cohort studies with a Extrapolated evidence from studies rated as 2+
high risk of confounding, bias or chance
and a significant risk that the relationship
is not causal Good practice point
3 Non-analytical studies, e.g. case reports,
Recommended best practice based on the
case series
clinical experience of the guideline
4 Expert opinion development group
RCOG Green-top Guideline No. 12 14 of 15 © Royal College of Obstetricians and GynaecologistsThis guideline was produced on behalf of the Guidelines Committee of the Royal College of Obstetricians and
Gynaecologists by:
Ms MC Davies FRCOG, London and Dr AL Jones, UCLH Foundation Trust, Cancer Management, London
and peer reviewed by:Association of Breast Surgery; British Maternal and Fetal Medicine Society; Breast Cancer Care;
RCOG Consumers’ Forum; Professor JM Dixon, Professor of Surgery and Consultant Surgeon,Western General Hospital,
Edinburgh, Scotland; Dr AHD Diyaf MRCOG, Birmingham; Dr A Francis, Consultant Breast Surgeon, University Hospital
Birmingham; Professor AB MacLean FRCOG, London; Professor J Lansac FRCOG, France; Professor P Sauven, Professor
of Surgical Oncology, Broomfield Hospital, Chelmsford, UK.
Committee lead peer reviewers were: Dr K Harding FRCOG, London and Dr NA Siddiqui FRCOG, Glasgow, Scotland.
Conflicts of interest: none declared
The final version is the responsibility of the Guidelines Committee of the RCOG.
The guidelines review process will commence in 2014, unless evidence requires earlier review
DISCLAIMER
The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical practice.
They present recognised methods and techniques of clinical practice, based on published evidence, for consideration by
obstetricians and gynaecologists and other relevant health professionals.The ultimate judgement regarding a particular
clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented
by the patient and the diagnostic and treatment options available.This means that RCOG guidelines are unlike protocols
or guidelines issued by employers, as they are not intended to be prescriptive directions defining a single course of
management. Departure from the local prescriptive protocols or guidelines should be fully documented in the patient’s
case notes at the time the relevant decision is taken.
RCOG Green-top Guideline No. 12 15 of 15 © Royal College of Obstetricians and GynaecologistsYou can also read
